A Role of Complement in the Pathogenic Sequelae of Mouse Neonatal Germinal Matrix Hemorrhage.

Mohammed Alshareef,Tyler Vasas,Ali Alawieh,Davis Borucki,Jonathan Cutrone,Stephen Tomlinson,Chelsea Shope,Ramin Eskandari,Khalil Mallah,Christine Couch

doi:10.3390/ijms23062943

Abstract

Germinal matrix hemorrhage (GMH) is a devastating disease of infancy that results in intraventricular hemorrhage, post-hemorrhagic hydrocephalus (PHH), periventricular leukomalacia, and neurocognitive deficits. There are no curative treatments and limited surgical options. We developed and characterized a mouse model of GMH based on the injection of collagenase into the subventricular zone of post-natal pups and utilized the model to investigate the role of complement in PHH development. The site-targeted complement inhibitor CR2Crry, which binds deposited C3 complement activation products, localized specifically in the brain following its systemic administration after GMH. Compared to vehicle, CR2Crry treatment reduced PHH and lesion size, which was accompanied by decreased perilesional complement deposition, decreased astrocytosis and microgliosis, and the preservation of dendritic and neuronal density. Complement inhibition also improved survival and weight gain, and it improved motor performance and cognitive outcomes measured in adolescence. The progression to PHH, neuronal loss, and associated behavioral deficits was linked to the microglial phagocytosis of complement opsonized neurons, which was reversed with CR2Crry treatment. Thus, complement plays an important role in the pathological sequelae of GMH, and complement inhibition represents a novel therapeutic approach to reduce the disease progression of a condition for which there is currently no treatment outside of surgical intervention.

Highlights

Germinal matrix hemorrhage (GMH) is the most common neurologic pathology in neonates, which is estimated at 3.5 per 1000 live births [1]
Germinal matrix hemorrhage often leads to intraventricular hemorrhage (IVH), resulting in post-hemorrhagic hydrocephalus (PHH) and periventricular leukomalacia [3]
A currently used procedure of surgical cerebrospinal fluid (CSF) diversion can mitigate the effects of PHH, but it does not cure the neurological disability caused by progressive damage from the hemorrhage, and there is life-long surgical morbidity in up to 90% of patients, including surgical infections and shunt malfunctions [7,8]

Summary

Introduction

Germinal matrix hemorrhage (GMH) is the most common neurologic pathology in neonates, which is estimated at 3.5 per 1000 live births [1]. It is caused by the disruption of fragile vasculature in the highly vascular subventricular zone (SVZ). Germinal matrix hemorrhage often leads to intraventricular hemorrhage (IVH), resulting in post-hemorrhagic hydrocephalus (PHH) and periventricular leukomalacia [3]. These two progressive pathological processes negatively impact neurodevelopmental processes and are highly associated with the development of cerebral palsy, with a rate of 30–42% of significant disability following severe GMH-IVH [4,5]. PHH contributes to significant neurologic disability as well as visual pathway disruption and papilledema, which is a feature that can be improved with CSF diversion as well [9,10]

Methods

Results

Conclusion